Combination therapy for preterm infants

Abstract

The present disclosure relates to a method of treating or preventing premature infants by intravenously administering a therapeutic amount of a composition comprising IGF-1 and IBGBP-3 in combination with a therapy selected from the group including caffeine, fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine, low dose norepinephrine, vancomycin at a concentration of 5 mg / ml or less, parenteral nutrition (or a composition for use therein), and combinations thereof.

Description

[Technical field]

[0001] The present disclosure relates to combination therapies that include, for example, IGF-1 and IBGBP-3 in complex with compatible drugs / medications and / or exclude incompatible drugs / medications. [Background technology]

[0002] background Preterm infants as a patient population are some of the most delicate, vulnerable and difficult to treat.

[0003] The rhIGF-1 / rhIGFBP-3 drug is a recombinant human (rh) version of the naturally occurring protein complex of insulin-like growth factor-1 (IGF-1) and its most abundant binding protein, insulin-like growth factor binding protein-3 (IGFBP-3). The product is currently under investigation for the prevention of complications in premature infants. It is administered parenterally, specifically by IV infusion. However, access to IV can be difficult, as premature infants admitted to the neonatal intensive care unit (NICU) typically require multiple IV therapies, including different classes of medications and parenteral nutrition (PN).

[0004] Historically, there has been a paucity of compatibility data available for drugs administered to preterm infants. A review of neonatal drug studies found that compatibility documentation was unavailable for nearly 60% of IV drug-drug infusions and 34% of IV drug-nutrient mixtures administered in the neonatal intensive care unit.

[0005] As expected, comprehensive drug testing in newborns is lacking. One US study reported that only 35% of medications administered to newborns were approved for use in infants by the US Food and Drug Administration, and an Italian study found that 44% of medications were prescribed off-label in the preterm neonatal population. Such findings may impact both efficacy and safety of treatment in infants. The majority of compatibility studies are performed for small molecules co-administered with small molecules. In contrast, the literature reveals compatibility testing for only two biologics, insulin and vasopressin, and no standard biologic-specific testing methods have been established.

[0006] Because rhIGF-1 / rhIGFBP-3 are infused continuously, compatibility with other medications is of paramount importance.

[0007] The inventors have demonstrated that commonly used medications can be co-administered with IGF-1 and IGFBP-3 to preterm infants, potentially improving the safety and efficacy of treatment, which is crucial for the health and survival of these delicate patients. Summary of the Invention [Problem to be solved by the invention]

[0008] [Means for solving the problem]

[0009] Effect of the Invention

[0010] A summary of the invention is provided in the following sections: 1. A method for the treatment or prevention of premature infants (also referred to herein as newborns) by intravenous administration of a therapeutic amount of a composition comprising IGF-1 and IBGBP-3, e.g., as a complex, in combination with a therapy or therapies selected from the group including caffeine (e.g., caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine (e.g., sulfate), low dose norepinephrine, vancomycin at a concentration of 5 mg / ml or less, parenteral nutrition (e.g., intravenous lipid emulsion, with or without electrolytes). 1A A composition of IGF-1 and IGFBP-3, e.g., as a complex, administered intravenously in combination with a therapy or therapies selected from the group including caffeine (e.g., caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine (e.g., sulfate), low dose norepinephrine, vancomycin at a concentration of 5 mg / ml or less, parenteral nutrition (e.g., intravenous lipid emulsion, with or without electrolytes) for the treatment or prevention of premature birth. 1B A composition of IGF-1 and IGFBP-3, e.g., as a complex, for use in the manufacture of a medicament for the treatment or prevention of preterm infants by intravenous administration in combination with a therapy or therapies selected from the group including caffeine (e.g., caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine (e.g., sulfate), low dose norepinephrine, vancomycin at a concentration of 5 mg / ml or less, parenteral nutrition (e.g., intravenous lipid emulsion, with or without electrolytes). 2. A method for the treatment or prevention of premature infants (also referred to herein as newborns) by intravenous administration of a therapeutic amount of a composition comprising IGF-1 and IBGBP-3 as a complex, for example, in combination with one or more further therapies (e.g., selected from the group including caffeine (e.g., caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine (e.g., sulfate), intravenous lipid emulsions, parenteral nutrition (e.g., intravenous lipid emulsions, with or without electrolytes), wherein the method of treatment or prevention is not concomitant administration of a therapy selected from amikacin sulfate, ampicillin sodium, dobutamine (e.g., hydrochloride), dopamine (hydrochloride), furosemide, meropenem, high doses of norepinephrine, penicillin G, vancomycin at a concentration greater than 5 mg / ml, and combinations thereof. 2A A composition of IGF-1 and IGFBP-3, e.g. as a complex, for the treatment or prevention of preterm infants by intravenous administration in combination with one or more further therapies (e.g. selected from the group including caffeine (e.g. caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine (e.g. sulfate), intravenous lipid emulsions, parenteral nutrition (e.g. intravenous lipid emulsions, with or without electrolytes)), wherein the further therapy is not concomitant administration of a therapy selected from amikacin (sulfate), ampicillin (sodium), dobutamine (e.g. hydrochloride), dopamine (hydrochloride), furosemide, meropenem, high dose norepinephrine, penicillin G, vancomycin (vancomycin injected at a concentration of 50 mg / mL or less). 2B A composition of IGF-1 and IGFBP-3, e.g. as a complex, for use in the manufacture of a medicament for the treatment or prevention of preterm infants by intravenous administration in combination with one or more further therapies (e.g. selected from the group including caffeine (e.g. caffeine citrate), fentanyl, fluconazole, gentamicin, insulin, midazolam, morphine sulfate, intravenous lipid emulsions, parenteral nutrition (e.g. intravenous lipid emulsions, with or without electrolytes), A composition of IGF-1 and IGFBP-3, wherein the additional therapy is not concomitant administration of a therapy selected from amikacin (sulfate), ampicillin (sodium), dobutamine (e.g., hydrochloride), dopamine (hydrochloride), furosemide, meropenem, high dose norepinephrine, penicillin G, vancomycin (injected at a concentration of 50 mg / mL or less). 3. The method or composition according to any of paragraphs 1 to 2, wherein the combination therapy is administered simultaneously (eg, delivered via the same IV line). 4. The method or composition according to any one of paragraphs 1 to 3, wherein IGF-1 and IBGBP-3 are administered in combination with caffeine (eg, caffeine citrate). 5. The method or composition according to any one of items 1 to 4, wherein IGF-1 and IBGBP-3 are administered in combination with fentanyl. 6. The method or composition according to any one of items 1 to 5, wherein IGF-1 and IBGBP-3 are administered in combination with fluconazole. 7. The method or composition according to any one of items 1 to 6, wherein IGF-1 and IBGBP-3 are administered in combination with gentamicin. 8. The method or composition according to any one of items 1 to 7, wherein IGF-1 and IBGBP-3 are administered in combination with insulin. 9. The method or composition according to any one of items 1 to 8, wherein IGF-1 and IBGBP-3 are administered in combination with midazolam. 10. The method or composition according to any one of paragraphs 1 to 9, wherein IGF-1 and IBGBP-3 are administered in combination with morphine (eg, sulfate). 11. The method or composition according to any one of items 1 to 10, wherein IGF-1 and IBGBP-3 are administered in combination with a low dose of norepinephrine. 12. The method or composition according to any of paragraphs 1 to 11, wherein IGF-1 and IBGBP-3 are administered in combination with vancomycin injected at a concentration of 5 mg / mL or less, for example less than 5 mg / mL. 13. The method or composition according to any of paragraphs 1 to 12, wherein IGF-1 and IBGBP-3 are administered in combination with not more than 50 mg / ml vancomycin administered as an infusion. 14. The method or composition according to any of items 1 to 13, wherein IGF-1 and IBGBP-3 are administered in combination with parenteral nutrition (eg, intravenous lipid emulsion, with or without electrolytes). 15. The method or composition of any one of clauses 2 to 14, wherein the additional, non-concurrently administered therapy is administered via a different IV line or a different route of administration, for example, intramuscular administration. 16. The method or composition according to any one of clauses 2 to 14, wherein further non-concurrently administered therapy is omitted entirely. 17. The method or composition according to any one of items 1 to 16, wherein the treatment of a premature infant is initiated within the range of 23 to 34 weeks after conception. 18. A method or composition according to any of the preceding paragraphs, wherein the premature infant is administered IGF-1 and IGFBP3 by infusion, e.g. by continuous infusion, in particular for at least 1 week, such as 2 to 6 weeks, e.g. 2, 3, 4, 5 or 6 weeks. 19. The method or composition of claim 18, wherein the infusion is initiated within 24 hours of birth, such as within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 hours of birth, in particular within 1 hour of birth. 20. The method or composition according to any one of paragraphs 1 to 19, wherein the composition comprises equimolar amounts of IGF-1 and IGFBP-3. 21. The method or composition according to any one of items 1 to 20, wherein 200 to 500 μg / Kg / 24 hours of IGF-1 and IGFBP-3 complex is administered. 22. The method or composition according to any one of items 1 to 21, wherein 22.55 to 110 μg / Kg / 24 hours of IGF-1 is administered. 23. The method or composition according to any one of items 1 to 22, wherein the serum level of IGF-1 is maintained in the range of 28 to 109 ng / ml. 24. The method or composition according to any one of items 1 to 23, wherein the low dose of norepinephrine is 0.05 μg / Kg / min or less. 25. The method or composition according to any one of items 1 to 23, wherein the composition comprising IGF-1 and IGFBP3 has a pH of 5.5±about 0.3, for example, a pH within the range of 5.2 to 5.8.

[0011] The non-combination therapy is incompatible with or unstable for formulation or delivery in admixture with IGF-1 / IGFBP-3.

[0012] As used herein, "not co-administered" refers to not being or not (has not been) administered, particularly not by the same route.

[0013] As used herein, IGF-1 / rhIGFBP-3 therapy generally refers to recombinant human (rh) insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) as a 1:1 complex, more specifically, complexed in a range of 0.75-1.25:1 or 1:0.75-1.25.

[0014] In one embodiment, the IGF-1 / IGFBP-3 therapy is administered continuously.

[0015] In one embodiment, the combination therapy is administered sequentially.

[0016] As used herein, therapy includes parenteral nutrition.

[0017] As used herein, "combination" (also called combination therapy) refers to co-formulation, mixing or co-administration, particularly co-administration by the same route.

[0018] "Generally, unless the context indicates otherwise, a combination refers to a compatible combination."

[0019] As used herein, a "compatible combination" refers to agents / ingredients / components that are suitable for combined delivery / administration, e.g., the components are at least physically and chemically stable when mixed and / or co-formulated.

[0020] Concurrent administration as used herein refers to delivery / administration at the same time, particularly by the same route, such as IV, particularly via the same IV line. Thus, co-administered agents may be present, for example, in the IV and / or IV bag at the same time.

[0021] In one embodiment, the co-administered agents are in separate formulations.

[0022] As used herein, a co-formulation refers to a single pharmaceutical formulation that contains two or more drugs.

[0023] As used herein, admixture refers to formulations / medications that are mixed at or immediately prior to administration, i.e., extemporaneously mixed, including mixing in an IV line or bag, for example, by adding medication to one already dispensed.

[0024] In one embodiment, combination therapy as used herein refers to a therapy that is compatible for delivery with IGF-1 / IGFBP-3, particularly one that is stable when delivered in the same formulation, in an admixture, or via the same route (such as the same IV line).

[0025] In one embodiment, the combination therapy used in the present disclosure is delivered in admixture, i.e., together, at the same time, and the stability of the combination drug is sufficient to allow this.

[0026] In one embodiment, the compatible drug / medicine is administered over a short period of time, for example, 1 to 30 minutes.

[0027] In an embodiment, the compatible drug / agent is administered for the same period as the IGF-1 / IGFBP-3.

[0028] In one embodiment, the stability is physical stability.

[0029] In one embodiment, the stability is chemical stability.

[0030] In one embodiment, the activity of the entity (such as IGF-1 / IGFBP-3 and / or other agent(s)) is stable, in particular the activity is not decreased.

[0031] In one embodiment, the agent is thermally stable at storage temperatures, such as, for example, 4° C. to room temperature.

[0032] In one embodiment, the stability is concentration dependent.

[0033] Changes in physical stability include aggregation, flocculation, and bombardment of particles out of solution.

[0034] Changes in chemical stability include degradation, changes in surface charge, changes in pH, etc.

[0035] Non-combination therapy is generally not stable in admixture with IGF-1 / IGFBP-3. In some embodiments, if available, the additional therapy can be administered separately, for example, via a separate IV line or subcutaneously. Alternatively, administration of IGF-1 / IGFBP-3 can be discontinued to allow administration of non-combination therapy. In one embodiment, administration of IGF-1 / IGFBP-3 is resumed after administration of non-combination therapy. If this is not available, administration of the incompatible therapy should be avoided.

[0036] In one aspect, the invention employs the formulations of IGF-1 and IGFBP-3 described in WO2022 / 086953, which is incorporated herein by reference. The formulation parameters disclosed may be used as the basis for amendments to the claims.

[0037] In some embodiments, the present disclosure employs a pharmaceutical composition comprising a protein complex comprising recombinant insulin-like growth factor 1 (rIGF-1), recombinant insulin-like growth factor binding protein 3 (rIGFBP-3), and a surfactant at a concentration of about 0.001%-2.4% v / v (such as 0.0025%-0.0075%, particularly about 0.005%), wherein rIGF-1 and rIGFBP-3 are complexed in equimolar amounts, for example, in the range of 0.75-1.25:1 or 1:0.75-1.25.

[0038] In some embodiments, the surfactant is a polysorbate surfactant, such as polysorbate 20 (also known as polyoxyethylene sorbitan monolaurate) or polysorbate 80 (also known as polyoxyethylene sorbitan monooleate).

[0039] In some embodiments, the polysorbate surfactant is polysorbate 20.

[0040] In some embodiments, the polysorbate surfactant is polysorbate 80.

[0041] In some embodiments, the polysorbate surfactant is at a concentration of about 0.001% to 2.4% v / v, such as about 0.2% to 0.4%.

[0042] In some embodiments, the polysorbate surfactant is at a concentration of about 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.01%, 0.02%, 0.03%, 0.05%, 0.10%, 0.15%, 0.2%, 0.5%, 0.7%, 1.0%, 1.2%, 1.5%, 1.8%, 2.0%, 2.2% or 2.4% v / v.

[0043] In some embodiments, the polysorbate surfactant is at a concentration of about 0.0025% to 0.0075%, such as about 0.0025%, about 0.005%, or about 0.0075% v / v, particularly about 0.005% v / v.

[0044] In one aspect, the present disclosure relates to a kit comprising a combination therapy according to the present disclosure.

[0045] In one embodiment, the high dose norepinephrine is 2.0 μg / Kg / min or greater.

[0046] In one embodiment, the high dose norepinephrine is 1.0 μg / Kg / min or greater.

[0047] In one embodiment, the high dose norepinephrine is greater than 0.05 μg / Kg / min.

[0048] In one embodiment, the low dose norepinephrine is 1.0 μg / Kg / min or less.

[0049] In one embodiment, the drug compatibility data is disclosed on the drug packaging of the IGF-1 / IGFBP-3, on an accompanying leaflet, on a website with product information therefor, etc.

[0050] In one embodiment, IV administration according to the present disclosure is used in combination with surfactant therapy. Surfactants, also known as rescue surfactants, include beractants.

[0051] As used herein, "is" means comprising.

[0052] In the context of this specification, "comprising" should be interpreted as "including".

[0053] Embodiments of the invention comprising particular features / elements are also intended to extend to alternative embodiments that "consist" or "consist essentially of" the associated element / feature.

[0054] Where technically appropriate, embodiments of the invention may be combined.

[0055] Technical references, such as patents and applications, are incorporated herein by reference.

[0056] Any embodiment specifically and explicitly described herein may, either alone or in combination with one or more further embodiments, form the basis of a disclaimer.

[0057] The Background section may be used as the basis for amendments.

[0058] This application claims priority to U.S. Patent No. 63 / 338,221, filed May 4, 2022, which is incorporated herein by reference, and in particular the sequences are expressly incorporated herein. The priority document may be used to correct errors in this specification.

[0059] The invention will now be further described, by way of example only, in the following examples which refer to the accompanying drawings, in which: [Brief description of the drawings]

[0060] [Figure 1] Figure 1. Risk assessment design. RP-HPLC reversed-phase high-performance liquid chromatography, SEC-HPLC size-exclusion high-performance liquid chromatography, USP United States Pharmacopoeia. [Figure 2-7] Figure 2-7 shows the HPLC plot. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0061] Working Example In this study, we investigated the physical compatibility of rhIGF-1 / rhIGFBP-3 pharmaceuticals when mixed with frequently administered drugs. To obtain a complete picture of compatibility, we assessed chemical compatibility at the low molecule content level as part of a separate protein content / chemical modification study.

[0062] This study was undertaken to systematically evaluate and build a comprehensive body of data regarding the compatibility of rhIGF-1 / rhIGFBP-3 with commonly administered intravenous medications to aid clinicians in their decision-making regarding co-infusion of rhIGF-1 / rhIGFBP-3.

[0063] Drug compatibility studies should be performed as early as possible in the investigational phase of neonatal drugs to allow sufficient time for the findings to be communicated to clinical trials and ultimately for the adoption of the drug in clinical practice.

[0064] 1.0 Study Drugs Study drugs were selected based on clinical priorities (i.e., drugs frequently administered to neonates) identified by clinical experts and from the phase 2 clinical trial investigational sites. The 19 drugs included in the study were amikacin, ampicillin, caffeine citrate, dobutamine, dopamine, fentanyl citrate, fluconazole, furosemide, gentamicin, insulin, intravenous lipid emulsion, meropenem, midazolam, morphine sulfate, norepinephrine bitartrate, penicillin G, custom mixed PN solution (with or without electrolytes), PN solution + intravenous lipid emulsion, and vancomycin (Table 1 below). Most study drugs were small molecule drugs, but rhIGF-1 / rhIGFBP-3 (Takeda, Lexington, MA, USA) is a recombinant protein.

[0065] [Table 1]

[0066] 2.0 Risk Assessment Design and Overview The risk assessment methodology was developed by a cross-functional team consisting of clinicians, neonatal pharmacists, and representatives from product development departments of small molecules, biologics, and clinical research sponsors, as well as representatives from clinical operations. The risk assessment consisted of three successive stages (Figure 1): (1) in vitro testing to determine the physical and chemical compatibility of rhIGF-1 / rhIGFBP-3 with other drugs (small molecules only); (2) risk assessment of each study drug taking into account the known theoretical potential for chemical modification, the near isoelectric point of the protein when not in admixture (based on pH value and potential for chemical modification), and clinical mixing history (including coadministration with insulin, which shares significant homology with rhIGF-1); and (3) a risk plan based on an assessment of low, moderate, or high risk of incompatibility.

[0067] 3.0 Mixed Protocols Mixing models were developed to mix rhIGF-1 / rhIGFBP-3 and the test drug at one or more representative clinical doses. For all studies, mixing calculations were performed with appropriate normalization (time and neonatal weight) and a volume-based scheme was devised. These calculations used a dose of 250 μg / Kg / 24 hours (the dose used in the Phase 2 trial) and at least two bracket doses of the small molecule drug (Table 2). For each study, multiple controls were designed to represent the concentration and matrix after mixing of either rhIGF-1 / rhIGFBP-3 or the test drug. Controls were created by diluting the rhIGF-1 / rhIGFBP-3 drug product in its own formulation buffer (to adjust the concentration) or in the matrix of the small molecule to examine the effect of changes in the absence of the small molecule.

[0068] Where applicable, the mixing duration was based on the estimated volume of each study drug and umbilical catheter at the highest dose (normalized to the same weight) and the calculated mean infusion rate of rhIGF-1 / rhIGFBP-3 (e.g., a dose of 250 μg / kg / 24 h normalized to a 0.5 kg neonate and a target rhIGF-1 / rhIGFBP-3 protein concentration of 50 μg / mL) (Table 2). In all studies, regular sampling of the mixture and control solutions was performed. Furthermore, longer mixing periods were considered as a worst-case scenario (e.g., interruptions in clinical practice could lead to extended infusion periods) and the continuation of the observed phenomena that occurred at the beginning of the mixing.

[0069] When applicable, two dosing scenarios were assumed for the calculation of the mixing period. In the first scenario, each of the two drugs was administered by pump and the average of the two flow rates at the highest dose of the small molecule was selected. In the second scenario, only rhIGF-1 / rhIGFBP-3 was pumped and the study drug was infused for a relatively short period (approximately 15–30 min). For these scenarios, and for any other drugs that were not pumped or infused, regular observations and sampling were performed at selected time points (Table 2). [Table 2] TIFF2025514452000003.tif129132

[0070] 4.0 Physical Compatibility Physical compatibility assays were compared for test samples and corresponding control solutions. In line with existing literature, the following method, or a modified version thereof, was used to assess the physical compatibility of rhIGF-1 / rhIGFBP-3 with the drug to be mixed: visual observation (United States Pharmacopeia [USP] <790> ), optical density at 320 nm (USP <851> and <857> ), pH measurement (USP <791> ), and osmolality at room temperature (USP <785> ) was used.

[0071] The objective of the visual observations was to determine the presence of precipitation, visible particles, and flocculated material, as well as color change (compared to water) and / or gas formation, which are potential indicators of chemical modification(s).

[0072] All vials for physical compatibility testing were examined under the same lighting conditions against white and black backgrounds using both fluorescent and Tyndall lights (Spectralight III, Macbeth / X-Rite, Grand Rapids, MI, USA or MIH-DX, Bosch / Eisai Machinery, Waiblingen, Germany). Mixture and control samples were analyzed for appearance after mixing at specific time points (Table 1). For detection of turbidity, an indicator of submicroscopic protein aggregation, optical density measurements were performed at 320 nm using a UV-Visible spectrophotometer (SpectraMax M5, Molecular Devices, San Jose, CA, USA). Measurements were performed in triplicate for each sample at each time point using a quartz cuvette with a path length of 1 cm, and the average of these was recorded. The pH value was recorded three times for each solution using a calibrated pH meter (Model 215, Denver Instrument, Bohemia, NY, USA; Fischer Scientific Accumet XL150, Pittsburgh, PA, USA) and the average was reported. The osmolarity change after mixing at room temperature was recorded using a calibrated osmometer (Model 3250, Advanced Instruments, Norwood, MA, USA). Three measurements were taken and the average was recorded.

[0073] A test drug was considered physically compatible with rhIGF-1 / rhIGFBP-3 if no changes in color, sediment, turbidity, or gas evolution were observed, or if there were no clinically relevant changes in osmolality or pH.

[0074] A pH change of about ±0.3 of the mixture from the pH of the rhIGF-1 / rhIGFBP-3 drug product control (pH 5.5) was considered a change that could affect the quality of rhIGF-1 / rhIGFBP-3, in which case the small molecule drug product would be considered non-compliant and further protein-specific data would be required for evaluation. The range considered was based on the control and release specifications of rhIGF-1 / rhIGFBP-3 (5.5±0.3) and a priori knowledge of the potential degradation and known stability of the rhIGF-1 / rhIGFBP-3 drug product. Due to existing clinical practice and taking into account the release specifications of rhIGF-1 / rhIGFBP-3 (300±30 mOsmol / kg), a less stringent criterion was used to consider the change in osmolality value.

[0075] 5.0 Small Molecule Chemical Compatibility The concentrations of small molecule test drugs after mixing were assessed using either reversed-phase high-performance liquid chromatography (RP-HPLC) with ultraviolet (UV) detection or ion chromatography with electrochemical detection at the last specified time point(s) (Table 2) (USP monograph or modified). For example, the RP-HPLC-UV method was used for detection of most molecules, but for some molecules, such as amikacin and gentamicin, a modified version of the USP ion chromatography assay with electrochemical detection was used. For each drug, a qualification of the USP method was performed to ensure method specificity, linearity, reproducibility, and precision. An example chromatogram of one small molecule (gentamicin) is shown in the Supplementary Information. Chemical incompatibility was considered as a loss of approximately 10% or more of the small molecule content over the defined test period. Small molecule analysis for PN or lipids was not possible due to the complex nature of such mixtures.

[0076] 6.0 Chemical Compatibility of rhIGF-1 / rhIGFBP-3 To assess the chemical compatibility of rhIGF-1 / rhIGFBP-3 pharmaceuticals, a highly sensitive mass spectrometry-based protein-specific method was developed by Takeda. The development of the protein-specific method has been reported separately.

[0077] 7.0 Risk Assessment and Risk Planning A comprehensive risk assessment was completed for drugs that demonstrated in vitro (in)compatibility (see Risk Assessment Design and Overview in Methods for a description of the risk assessment). A risk event was defined as "rhIGF-1 / rhIGFBP-3 is incompatible with the co-infused drug over the duration and conditions of the simulated co-mixing study."

[0078] A risk assessment was performed for each co-infused study drug to determine the probability and severity of a risk occurrence. Probability was defined as the likelihood of an impact on safety, efficacy, or quality. Severity was defined as the severity of the impact if a risk event occurred (Table 3). A risk planning strategy was developed for each drug based on the level of probability and severity (low, moderate, or high) (Table 4). A cross-functional team of subject matter experts performed the final evaluation and approved the clinical recommendations.

[0079] [Table 3]

[0080] [Table 4]

[0081] 8.0 Results 8.1 In vitro physical compatibility Of the 19 drugs tested, physical compatibility of rhIGF-1 / rhIGFBP-3 with caffeine citrate, fentanyl, fluconazole, gentamicin, insulin, intravenous lipid emulsion, midazolam, morphine sulfate, PN solution + intravenous lipid emulsion, PN solution (with or without electrolytes), and vancomycin (when administered from a 5 mg / mL solution) was established (Table 5). The following drugs were considered incompatible with rhIGF-1: amikacin, ampicillin, dobutamine, dopamine, furosemide, meropenem, norepinephrine, penicillin G, and vancomycin (when administered from a 50 mg / mL solution).

[0082] [Table 5] TIFF2025514452000007.tif197132TIFF2025514452000008.tif95132

[0083] 8.2 Chemical Compatibility of Small Molecules Small molecule compatibility was not affected after mixing of the tested agents: no loss of small molecule content was observed for any of the tested agents in the mixtures and corresponding controls (Table 1 above).

[0084] 8.3 Risk Assessment and Risk Planning Risk assessments were completed for all small molecule test drugs (except for furosemide, for which the studied mixture became turbid within approximately 30 minutes, clearly demonstrating incompatibility with rhIGF-1 / rhIGFBP-3 drug products). Where in vitro physical compatibility was confirmed, subsequent risk assessments confirmed that the probability and severity of an event in the in-use setting was low. Risk of interaction or chemical modification based on pH value was also considered low for drugs showing in vitro compatibility.

[0085] Given the structural similarity between insulin and IGF-1, drug compatibility with insulin was given due consideration when evaluating the compatibility of the tested drugs with rhIGF-1 / rhIGFBP-3. For example, compatibility with insulin has been established for midazolam and vancomycin, suggesting a low risk of incompatibility with rhIGF-1 / rhIGFBP-3, but particular attention was paid to the low molecule concentrations evaluated for compatibility with insulin. No compatibility data are available to date for insulin with fentanyl or fluconazole, but based on theoretical evaluations and the pH of the solutions, no reaction is expected.

[0086] Among drugs found to be incompatible with rhIGF-1 / rhIGFBP-3 in in vitro studies, the risk was classified as moderate / high and appropriate measures were recommended.

[0087] [Table 6]

[0088] 8.4 Small molecule chemical compatibility For each drug, a qualification of the USP method (or a modified version thereof) was performed to ensure the specificity, linearity, reproducibility, and precision of the method. In this section, gentamicin is presented as an example. Amino sugar-based antibiotics such as gentamicin and related substances were analyzed by ion chromatography with electrochemical detection. The USP monograph for gentamicin content in gentamicin sulfate was modified to quantify the assay (concentration) of gentamicin sulfate. To obtain these results, several modifications were made to the USP monograph. Samples were quantified using a standard calibration of n=5 with a nominal standard concentration of 0.2 mg / mL gentamicin sulfate. The total area (group) of all gentamicin peaks was used to quantify the amount of gentamicin sulfate (mg / mL) in the sample. Mixture and control samples were then analyzed according to the method modified to support the study. Mixture samples were diluted with mobile phase to obtain a working concentration suitable for all samples. Table 6 summarizes the analytical parameters for the presented example. Figures 2-7 show representative chromatograms of gentamicin.

[0089] 9.0 Summary In this study, in vitro testing demonstrated physical compatibility of rhIGF-1 / rhIGFBP-3 medicinal products with 11 / 19 medications and nutritional therapies under the conditions and doses tested. For medications showing in vitro compatibility, risk assessment confirmed low probability and severity of risk of incompatibility. Physical compatibility was not established with 8 / 19 medications. For medications identified as incompatible, redistribution of infusion fluids is required to optimize available IV lines.

Claims

1. A mixed or concurrently formulated composition for use in a treatment including the prevention of premature complications in premature infants born between 23 and 34 weeks post-gestation at the start of treatment, wherein the composition is concurrently administered to the premature infant via the same IV line for concomitant therapy, and the concomitant therapy is Administering a composition containing IGF-1 and IGFBP-3 and a polysorbate surfactant selected from polysorbate 20 and polysorbate 80 at concentrations of approximately 0.0025% to 0.0075% v / v, at a dose of 200 to 500 μg / kg / 24 hours by continuous intravenous infusion, and i. Fentanyl citrate in doses selected from 0.5, 2, and 5 μg / kg / hour, ii. Midazolam hydrochloride in doses selected from 20 and 60 μg / kg / hour, iii. Morphine sulfate in doses selected from 5, 10, and 50 μg / kg / hour, iv. Norepinephrine bitartrate at a dose of 0.05 μg / kg / min, and v. Vancomycin hydrochloride at doses selected from 15 and 25 mg / kg / 60 mins Adaptive therapy selected from the essential group Includes, A composition for use wherein the combination therapy is physically and chemically stable, and the pH of the mixed or simultaneously formulated composition is 5.5 ± 0.

3.

2. The composition for use according to claim 1, wherein the IGF-1 and IGFBP-3 are administered in combination with fentanyl citrate.

3. The composition for use according to claim 1, wherein the IGF-1 and IGFBP-3 are administered in combination with midazolam hydrochloride.

4. The composition for use according to claim 1, wherein the IGF-1 and IGFBP-3 are administered in combination with a morphine sulfate.

5. The composition for use according to claim 1, wherein the IGF-1 and IGFBP-3 are administered in combination with norepinephrine bitartrate at a dose of 0.05 μg / kg / min.

6. The composition for use according to claim 1, wherein the IGF-1 and IGFBP-3 are administered in combination with vancomycin hydrochloride at a concentration of 5 mg / mL or less, in a dose selected from 15 and 25 mg / kg / 60 mins.

7. The composition for use according to claim 1, wherein the IGF-1 and IGFBP-3 are administered in combination with parenteral nutrition.

8. The composition for use according to claim 1, wherein further non-simultaneous therapies selected from amikacin, ampicillin, dobutamine, dopamine, furosemide, meropenem, high doses of norepinephrine, penicillin G, and vancomycin at concentrations greater than 5 mg / ml are administered by different IV lines or different routes of administration, for example, intramuscular administration.

9. The composition for use according to claim 1, wherein further non-simultaneous therapy is completely omitted.

10. The composition for use according to claim 1, wherein the premature infant is administered IGF-1 and IGFBP-3 for at least one week.

11. The composition for use according to claim 10, wherein IGF-1 and IGFBP-3 are administered for 2 to 6 weeks.

12. The composition for use according to claim 1, wherein the injection is initiated within 24 hours of birth.

13. The composition for use according to any one of claims 1 to 7, wherein the composition comprises equimolar amounts of IGF-1 and IGFBP-3.

14. The composition for use according to claim 1, wherein the osmotic pressure is 300 ± 30 mOsmol / kg.

15. The composition for use according to claim 1, wherein IGF-1 and IGFBP-3 are recombinant human (rh) insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3).

16. The composition for use according to claim 1, wherein the polysorbate surfactant is present at a concentration of about 0.005% v / v.

Images